Development of the nervous system is a complex process, involving coordinated regulation of diverse cellular processes including proliferation, differentiation and synaptogenesis. Disturbances to brain development such as pre- and perinatal
hypoxia have been linked to behavioural and late onset of
neurological disorders. This study examines the effect of
hypoxia on neurite outgrowth in PC12 cells.
Hypoxia not only caused a rapid induction of neurite outgrowth, but also synergistically enhanced
nerve growth factor (
NGF)-induced neurite outgrowth up to 24 h. Transactivation of TrkA receptors was ruled out since the TrkA inhibitor
K252a did not block
hypoxia-induced neurite outgrowth.
Adenosine deaminase prevented
hypoxia-induced neurite outgrowth indicating that the effect is mediated by
adenosine. Use of the specific
adenosine A2A receptor agonist
CGS21680 and antagonist 8-3(chlorostyryl)caffeine demonstrated that activation of this receptor is critical for
hypoxia-induced neurite outgrowth.
Hypoxia-induced neurite outgrowth was blocked by the
adenylate cyclase inhibitor,
MDL-12,330A, indicating a role for activation of this
enzyme in the pathway.
Hypoxia was further shown to cause a decrease in growth-associated
protein (GAP)-43 levels and a lack of induction of betaIII
tubulin, in contrast to
NGF treatment which resulted in increased cellular levels of both of these
proteins. These findings suggest that
hypoxia induces neurite outgrowth in PC12 cells via a pathway distinct from that activated by
NGF. Thus, exposure to
hypoxia at critical stages of development may contribute to aberrant neurite outgrowth and could be
a factor in the pathogenesis of certain delayed developmental
neurological disorders.